The present invention concerns a disposable measurement arrangement comprising a disposable container and a disposable measurement probe for measuring an analytical property of a medium and a method of testing and/or calibrating this arrangement.
Such arrangements are widely used in various branches of industry for example in the Pharmaceutical Industry, in Biotechnology, as well as in Medicine. They are for example used as bioreactors in Life Science Industry.
There is a wide range of analytical properties that need to be measured or monitored in these application, including for example a pH value, an Oxygen content, an oxidation reduction potential or a content of a specific ion.
In these branches of industry very high standards of hygiene are required. These standards may vary slightly from country to country, but in general they require, that any surfaces of the measurement arrangement, which may come in contact with the product can be effectively cleaned and/or sterilized.
In conventional measurement arrangements of this type, e.g. in bioreactors, closed systems are used. They comprise stainless steel vessels and the measurement probes are inserted through the metal ports into the vessel. The closed system is sterilized by hot steam or chemicals for a period of time to assure that all living organisms are inactivated. The bioreactor is cooled, dried and charged for example with media, cells, nutrients and gasses. The bioreaction is then started. Since the measurement probe was sterilized with the initial sterilization cycle of the system, the sterilized probe is in contact with the bioreaction media through the sidewall of the bioreactor. Electronic signals from the measurement probe are used for example to precisely control the analytical property measured therewith.
In order to avoid the time and costs involved in cleaning and/or sterilizing the closed system these Industries prefer to use presterilized disposable measurement arrangements.
The main advantage of disposable measurement arrangements is, that cleaning and sterilization of the equipment is no longer necessary. Disposable presterilized systems can be kept on stock. This allows for a great flexibility and time efficiency, especially when production lines need to be set up, enlarged or scaled down frequently.
Today, there is a wide range of disposable flexible containers on the market. They are for example manufactured by companies such as HyClone, Logan, Utah, USA or Sartorius BBI Systems GmbH, Germany. Disposable single use containers usually comprise a large flexible bag with aseptic connections for the attachment of tubing. The empty disposable containers are typically sterilized with gamma radiation and delivered to the user. The user attaches sterile tubing to the container via the aseptic connections which allow the connection of presterilized components without breaching sterility of the components. The user then adds media, e.g. cells and nutrients, and runs the process. At the end of the process, the disposable container is emptied and discarded.
In order to measure analytical properties of a medium inside the container, it is possible, to install corresponding measurement probes inside the container and to sterilize the measurement probe together with the container using gamma radiation.
Measurement probes for measuring the analytical properties, like the ones listed above, usually comprise a sensitive sensing element, that needs to be hydrated before use, in order to perform accurate measurements. In particular, they comprise electrochemical cells, having sensitive electrodes, membranes or diaphragms, which need to be hydrated during storage. If they are not hydrated prior to measurement, the sensing element will need time to adapt when immersed into the fluid to be measured, until a chemical equilibrium is established.
Hydration of the sensing elements of such measurement probes can be performed by inserting the probe into a buffer solution. With respect to the above mentioned measurement arrangement, where the probe is already built into the disposable container, this cannot be done without breaching the sterility of the arrangement.
In the International Patent Application WO 2004/059286 a method is described wherein a pH probe is inserted in a buffer solution, gamma sterilized and packaged together with the buffer solution. In order to use such a hydrated probe in the measurement arrangement under consideration, the probe would need to be unpacked and taken out of the buffer solution prior to installing it inside the disposable container. Since this installation would most likely breach the sterility of the arrangement, the entire arrangement will need to be sterilized again. Consequently the probe would begin to dry up during sterilization. If the measurement arrangement is not used immediately after sterilization, the sensing element of the probe will dry up again during storage of the measurement arrangement.
In addition, it has not been possible to use buffer solutions to validate that the measurement probe is functional or to perform a calibration of the measurement probe after it has been installed and sterilized inside the disposable container. In conventional measurement arrangements, tests and/or calibration procedures using buffer solutions can only be performed prior to the insertion of the measurement probe into the disposable container or into conventional bioreactors.
It is an object of the invention to provide a measurement arrangement comprising a sterile disposable container and a sterile measurement probe for measuring an analytical property of a product, wherein said measurement arrangement is ready to use and produces reliable measurement results.
To this end the invention comprises a disposable measurement arrangement comprising:                a flexible disposable plastic container,        a disposable measurement probe for measuring an analytical property of a medium, mounted on an inside wall of said disposable container, comprising a sensing element extending into the container,        a closed capsule containing a buffer solution, and        a tether connecting said capsule to said probe, wherein        said container, said measurement probe, said capsule and said buffer solution are sterilized;        said sensing element is inserted in said buffer solution during storage, and        said capsule is removed from the sensing element during measurement operation.        
According to a preferred embodiment, the measurement probe is a pH probe, an Oxygen content measurement probe, a specific ion concentration measurement probe or an oxidation reduction potential measurement probe.
According to a preferred embodiment, the measurement arrangement further comprises                at least one additional closed capsule containing a reference medium having a known analytical property,        said additional capsule comprising means for allowing for said sensing element to be inserted into said reference medium; and        means for attaching said additional capsule to said probe.        
According to a preferred embodiment, said means for allowing for said sensing element to be inserted into said reference medium comprise a piercable membrane or a removable lid that is tethered to the assembly.
The invention further comprises a method of testing and/or calibrating a disposable measurement probe of a disposable measurement arrangement according to the invention, wherein                said buffer solution has a known analytical property,        said sensing element is inserted into said buffer solution during testing and/or calibration,        said analytical property of said buffer solution is measured with said measurement probe, and        said measured analytical property is compared to said known analytical property of said buffer solution.        
According to a preferred embodiment of this method, an Off Set of the measurement probe is adjusted based on said comparison of said measured analytical property and said known analytical property of said buffer solution.
The invention further comprises a method of calibrating a disposable measurement probe of a disposable measurement arrangement according to the invention, wherein                said measurement arrangement comprises at least two capsules,                    each containing a different reference medium having a known analytical property, and            each comprising means for allowing for said sensing element of said measurement probe to be inserted into said reference medium during a calibration procedure; comprising the steps of                        consecutively inserting said sensing element of said measurement probe into each of the reference media,        measuring said analytical property of each reference medium with the probe whilst said sensing element is inserted in said reference medium, and        comparing said measured analytical properties to the known analytical properties of the reference media.        
According to a preferred embodiment of the last mentioned method, an Off Set and a Span of said measurement probe is adjusted based on said comparisons of said measured analytical properties and said known analytical properties of said reference media.
The invention further comprises a method of calibrating a disposable measurement probe of a disposable measurement arrangement according to the invention, wherein                said measurement probe is an Oxygen content measurement probe, and        said disposable container contains at least a small amount of sterile air having a known Oxygen content, comprising the step of:        removing said sensing element of said probe from said capsule containing said buffer solution,        exposing said sensing element of said probe to said sterile air,        measuring an Oxygen content of said air with said measurement probe and comparing said measured Oxygen content to said known Oxygen content.        
The invention further comprises a method of removing a capsule from the measurement probe or of mounting a capsule on said disposable measurement probe of said measurement arrangement according to the invention, wherein said capsule is manually grasped through the flexible container wall and pulled of or inserted onto the measurement probe.
According to a preferred embodiment of the invention, said capsule containing the buffer solution contains a sponge like material that is saturated with the buffer solution, and each additional capsule containing a reference medium contains a sponge like material that is saturated with the reference medium.
It is an advantage of the invention, that the calibration of the measurement probe can be validated on site utilizing the buffer solution and/or the reference media.
The invention and further advantages are explained in more detail using the figures of the drawing, in which two exemplary embodiment are shown. The same reference numerals refer to the same elements throughout the figures.